The goal of this application for a High Risk Rheumatic and Musculoskeletal and Skin Diseases Research grant is to develop a strategy for studying early synovitis and provide a framework to test the window-of-opportunity hypothesis in the treatment of rheumatoid arthritis (RA). RA is a chronic inflammatory arthritis that can lead to deformity and disability. Among drugs to treat RA, DMARDs (disease modifying anti-rheumatic drugs) can improve the signs and symptoms of arthritis and prevent or slow the destruction of cartilage and bone that leads to deformity. Since early treatment with DMARDs improves clinical outcomes, there is a strong rationale for instituting these agents early in the course of disease. Such early use, however, is complicated by diagnostic uncertainty, including the difficulties in differentiating patients with RA from those with inflammatory arthropathies other than RA as well as the occurrence of remission in early disease. Furthermore, efforts to institute therapy early may be limited by delays in patients seeking care as welt as provider uncertainty or reluctance to begin DMARDs early. Resolution of these issues can be best accomplished in the context of a comprehensive program of clinical research that will ultimately include a clinical trial to assess the window-of-opportunity hypothesis. This hypothesis states that the aggressive treatment of synovitis early in disease may prevent the emergence of RA or other persistent synovitis. At present, there is national and international interest in the conduct of such a trial and the opportunities it provides for addressing critical issues in disease pathogenesis. This high-risk grant will therefore address fundamental questions in the recruitment and identification of patients with early disease and establish the basis for a clinical trial. Three specific aims are proposed: 1) to develop a clinical trial to test the window-of-opportunity hypothesis; 2) to test recruitment of patients in a pilot study; and 3) to assess ethical issues of early intervention. [unreadable] [unreadable] [unreadable]